Along with the HMG-CoA reductase (see Illingworth, D. R., "Specific . . . as hypocholesterolemic agents in humans", Mevinolin and Compactin" in Pharmacological Control of Hyperlipidaemia, J. R. Prous, Science Publishers (1986), pp. 231-249) and 7-alpha hydroxylase (see Cighetti, G. et al, "The effect . . . cholesterol 7-alpha hydroxylase . . . animals" in Life Science, 33 (1983), pp. 2483-2488) enzymes, acylCoA:cholesterol acyltransferase (ACAT, EC 2.3.1.26), which latter enzyme is found in virtually all tissue but demonstrating highest activity in tissues such as the liver, intestine, adrenal and atherosclerotic arterial tissue, is known to be one of the major regulators of cholesterol metabolism in warm-blooded animal cells. Since the accumulation of esterified cholesterol is one of the characteristic features of atherosclerotic plaque (see Bell, F. P., "Arterial Cholesterol Esterification . . . Inhibition By Drugs", in Pharmacological Control of Hyperlipidaemia (1986), J. R. Prous, Science Publishers, pp. 409-422), the regulation of the ACAT enzyme activity is believed to be of significant importance in the treatment of atherosclerosis and related diseases in valuable animals including humans.
The ACAT enzyme is a constitutive protein in the endoplasmic reticulum and as such can be dramatically influenced by alterations in membrane fatty acid composition, phospholipid composition and cholesterol content (see Bell, F. P., supra; Doolittle, G. M. et al, "Solubilization . . . of AcylCoA:cholesterol Acyltransferase" in Biochemistry, 21 (1982), pp. 674-679, and Brenneman, D. E. et al, "Effects of Dietary Fat . . . Microsomes" J. Lipid Research, 18 (1977), pp. 583-591). It is recognized in the art that when such alteration or modifications in membrane fatty acid composition are extensive enough to alter membrane fluidity a number of cellular functions, which include among others, carrier-mediated transport, the properties of certain membrane-bound enzymes, binding to insulin and opiate receptors, etc., are affected.
An example of a known drug that has been shown to change the fluidity of membranes and is also an ACAT enzyme inhibitor is the tranquilizer, chlorpromazine (see Keefe, E. B. et al, "Alteration . . . By Chlorpromazine . . . ", Gastroenterology, 79, (1980), pp. 22-231; Ogiso, T. et al, "Fluidity . . . Chlorpromazine . . . Membrane", in Biochim. Biophys. Acta, 649 (1981), pp. 325-335 and Bell, F. P., "Effect of Chlorpromazine . . . Synthesis" in Exp. Molec. Pathol., 38 (1983), pp. 336-346). Chlorpromazine is also known to have blood platelet aggregation inhibition properties (see Jain, M. K. et al, "Correlation of Inhibitors . . . Bilayer" in Thrombosis Res., 13 (1978), pp. 1067-1075).
Other known drug compounds which also have ACAT enzyme inhibiting activity include the sedative-tranquilizer, diazepam, and the beta-blocker compound propanolol (see Bell, F. P., "Effects . . . Propanol . . . on ACAT Activity . . . Vitro", in J. Cardiovasc. Pharmacol., 7 (1985), pp. 437-442).
6-Cyclohexyl-4,7-dihydro-2-phenyl-5H-pyrazolo[1,5-a]pyrrolo[3,4-d]pyrimidin e-5,8(6H)-dione, utilized as a starting material to prepare compounds of this invention, was once commercially available. However, this compound is inactive in the ACAT enzyme screen.
Those in the art continue to search for new compounds which will be more potent as ACAT enzyme inhibitor compounds than known ACAT inhibitor drugs and/or drugs which will have no or fewer other drug property side effects.